5&#39;-deoxy-cytidine derivatives

ABSTRACT

Novel 5&#39;-deoxy-cytidine derivatives represented by the general formula (I) ##STR1## wherein R 1  is a hydrogen atom or a group easily hydrolyzable under physiological conditions; R 2  is a hydrogen atom, or --CO--OR 4  group [wherein R 4  is a saturated or unsaturated, straight or branched hydrocarbon group consisting of one to fifteen carbon atoms, or a group of the formula --(CH 2 ) n  --Y (in which Y is cyclohexyl or phenyl; n is an integer from 0 to 4)]; R 3  is a hydrogen atom, bromo, iodo, cyano, a C 1-4  alkyl group [which may be substituted with halogen atom(s)], a vinyl or ethynyl group [which may be substituted with halogen atom(s), C 1-4  alkyl, cycloalkyl, aralkyl, or aromatic ring which may have one or more hetero atom(s)], or an aralkyl group which may be substituted for use in medical therapy, especially tumor therapy.

This is a continuation of copending application Ser. No. 09/088,668,filed on Jun. 2, 1998.

FIELD OF THE INVENTION

The present invention is concerned with novel 5'-deoxy-cytidinederivatives, pharmaceutical compositions, a kit thereof for assisting adelivery of 5-fluorouracil selectively to tumor tissues and process formanufacturing the novel 5'-deoxy-cytidine derivatives.

BACKGROUND

Although 5-fluorouracil (5-FU) or its derivatives are clinically usefulantitumor agents for the treatment of various solid tumors, in generalthey are still not satisfactory in terms of efficacy and safety. Thesedrawbacks are mainly due to rapid inactivation of 5-FU bydihydropyrimidine dehydrogenase (DPD) and/or the unsatisfactory deliveryof 5-FU to tumor tissues with respect to tumor selectivity. The attemptsto enhance the antitumor activity of 5-FU or its derivatives byinhibition of DPD have already been reported : the co-administration of5-FU or its derivative with a DPD inhibitor such as uracil [U.S. Pat.No. 4,328,229], 5-ethynyluracil [WO92/04901],5-chloro-2,4-dihydroxypyridine [U.S. Pat. No. 5,525,603] etc. Suchco-administration resulted in enhancement of the antitumor activity of5-FU or its derivatives, but the safety profile was not so improved dueto insufficient selectivity in delivering the DPD inhibitor to tumortissues (as a consequence, 5-FU level is increased both in tumor andplasma).

SUMMARY OF THE INVENTION

The present invention relates to 5'-deoxy-cytidine derivatives of theformula (I), ##STR2## wherein R¹ is a hydrogen atom or a group easilyhydrolyzable under physiological conditions; R² is a hydrogen atom, or--CO--OR⁴ group [wherein R⁴ is a saturated or unsaturated, straight orbranched hydrocarbon group consisting of one to fifteen carbon atoms, ora group of the formula --(CH₂)_(n) --Y (in which Y is cyclohexyl orphenyl; n is an integer from 0 to 4)]; R³ is a hydrogen atom, bromo,iodo, cyano, a C₁₋₄ alkyl group [which may be substituted with halogenatom(s)], a vinyl or ethynyl group [which may be substituted withhalogen atom(s), C₁₋₄ alkyl, cycloalkyl, aralkyl, or aromatic ring whichmay have one or more hetero atom(s)], or an aralkyl group which may besubstituted; with the proviso that R² and R³ do not simultaneously meana hydrogen atom.

The present invention also relates to pharmaceutical compositionscomprising a 5'-deoxy-cytidine derivative of formula (I) and apharmaceutically acceptable inert carrier material.

In accordance with the present invention it has been found that theco-administration of a 5'-deoxy-cytidine derivative of the formula (I)with 5-FU or its derivative results in the significantly improveddelivery of 5-FU selectively to tumor tissues as compared with thecombination of 5-FU or its derivative with a known DPD inhibitor such as5-ethynyluracil, and shows significantly improved antitumor activity inhuman cancer xenograft models.

The present invention also relates to pharmaceutical compositionscomprising a 5'-deoxy-cytidine derivative of formula (I) and5'-fluorouracil or a derivative thereof.

DETAILED DESCRIPTION OF THE INVENTION

The respective groups of the formula (I) are explained in more detail asfollows;

Explanation of R¹ :

R¹ is a hydrogen atom or a group easily hydrolyzable under physiologicalcondition.

In the above, the term "a group easily hydrolyzable under physiologicalcondition" preferably means acetyl, propionyl, benzoyl, toluoyl, glycyl,alanyl, β-alanyl, valyl, lysyl, and the like. In the most preferredembodiment of the compounds in accordance with the present invention, R¹means hydrogen, or acetyl.

Explanation of R² :

R² is a hydrogen atom, or --CO--OR⁴ group [wherein R⁴ is a saturated orunsaturated, straight or branched hydrocarbon group consisting of one tofifteen carbon atoms, or group of formula --(CH₂)_(n) --Y (in which Y iscyclohexyl or phenyl; n is an integer of from 0 to 4)].

In the above group R⁴, the term "a saturated or unsaturated, straight orbranched hydrocarbon group consisting of one to fifteen carbon atoms"preferably means methyl, ethyl, n-propyl, 1-isopropyl-2-methylpropyl,1,1,2-trimethylpropyl, n-butyl, isobutyl, 2-ethylbutyl,3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, 2-propylpentyl,n-hexyl, 2-ethylhexyl, n-heptyl, n-octyl, allyl, 2-buten-1-yl,3-buten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 3-hexen-1-yl, 4-hexen-1-yl,5-hexen-1-yl, n-tridecyl and the like.

The term "a group of the formula --(CH₂)_(n) --Y (in which Y iscyclohexyl or phenyl; n is an integer from 0 to 4)" preferably meanscyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl,4-cyclohexyl-butyl, phenyl, benzyl, phenethyl, 3-phenylpropyl,4-phenylbutyl and the like.

In the most preferred embodiment of the compounds in accordance with thepresent invention, R⁴ means n-propyl, n-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, 3,3-dimethylbutyl, 2-ethylbutyl, phenylethyl, andcyclohexylmethyl.

Explanation of R³ :

R³ is a hydrogen atom, bromo, iodo, cyano, a C₁₋₄ alkyl group [which isunsubstituted or substituted with one or more halogen atom(s)], a vinylor ethynyl group [which is unsubstituted or substituted with one or morehalogen atom(s), C₁₋₄ alkyl, cycloalkyl, aralkyl, or aromatic ring whichmay have one or more hetero atom(s)], or an aralkyl group which isunsubstituted or substituted; with the proviso that R² and R³ do notmean a hydrogen atom at the same time.

In the above, the term "a C₁₋₄ alkyl group which is unsubstituted orsubstituted with one or more halogen atom(s)" preferably means methyl,trifluoromethyl, ethyl, propyl and the like.

The term "a vinyl or ethynyl group [which is unsubstituted orsubstituted with one or more halogen atom(s), C₁₋₄ alkyl, cycloalkyl,aralkyl, or aromatic ring which may have one or more hetero atom(s)]"preferably means vinyl, 1-chlorovinyl, 2-bromovinyl,2-bromo-1-chlorovinyl, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1 -ynyl,hex-1 -ynyl, 3,3-dimethyl-but-1 -ynyl, cyclopentylethynyl,cyclohexylethynyl, phenylethynyl, 3-phenylprop-1-ynyl,pyrid-2-ylethynyl, imidazol-2-ylethynyl, and the like. The mostpreferred group is ethynyl, vinyl and iodo.

The term "an aralkyl group which is unsubstituted or substituted"preferably means 3-(benzyloxy)benzyl, 3-methoxybenzyl, 3-bromobenzyl,3-methylbenzyl, 3-hydroxybenzyl and the like.

Preferred 5'-deoxy-cytidine derivatives of the present invention are:

5'-deoxy-5-ethynylcytidine,

5'-deoxy-5-prop-1-ynylcytidine,

5-but-1-ynyl-5'-deoxycytidine,

5'-deoxy-5-pent-1-ynylcytidine,

5'-deoxy-5-hex-1-ynylcytidine,

5'-deoxy-5-iodocytidine,

5-bromo-5'-deoxycytidine,

5-(1-chlorovinyl)-5'-deoxycytidine,

5'-deoxy-5-vinylcytidine,

5'-deoxy-5-trifluoromethylcytidine

5-(3-benzyloxybenzyl)-5'-deoxycytidine,

5-cyano-5'-deoxycytidine,

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-prop-1-ynylcytidine,

5-but-1-ynyl-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-pent-1-ynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-hex-1-ynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-iodo-N⁴ -(n-pentyloxycarbonyl)cytidine,

5-bromo-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine,

5-(1-chlorovinyl)-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine,

N⁴ -(ethoxycarbonyl)-5'-deoxy-5-vinylcytidine,

5'-deoxy-N⁴ -(n-propoxycarbonyl)-5-vinylcytidine,

N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-vinylcytidine,

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-vinylcytidine,

N⁴ -(benzyloxycarbonyl)-5'-deoxy-5-vinylcytidine,

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-trifluoromethylcytidine,

5-(3-benzyloxybenzyl)-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine,

5-cyano-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-ethynyl-N⁴ -(methoxycarbonyl)cytidine

5'-deoxy-N⁴ -(ethoxycarbonyl)-5-ethynylcytidine

5'-deoxy-5-ethynyl-N⁴ -(n-propoxycarbonyl)cytidine,

5'-deoxy-5-ethynyl-N⁴ -(isopropoxycarbonyl)cytidine,

N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-ethynylcytidine,

5'-deoxy-5-ethynyl-N⁴ -(isobutoxycarbonyl)cytidine,

5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-ethynyl-N⁴ -[(2-propylpentyloxy)carbonyl]cytidine,

5'-deoxy-5-ethynyl-N⁴ -(isopentyloxycarbonyl)cytidine,

5'-deoxy-5-ethynyl-N⁴ -[(2-methylpentyloxy)carbonyl]cytidine,

5'-deoxy-5-ethynyl-N⁴ -[(3-methylpentyloxy)carbonyl]cytidine,

5'-deoxy-5-ethynyl-N⁴ -(n-hexyloxycarbonyl)cytidine,

5'-deoxy-N⁴ -[(2-ethylbutyl)oxycarbonyl]-5-ethynylcytidine,

5'-deoxy-N⁴ -[(2-ethylhexyl)oxycarbonyl]-5-ethynylcytidine,

5'-deoxy-5-ethynyl-N⁴ -[(2-phenylethoxy)carbonyl]cytidine,

N⁴ -(cyclohexyloxycarbonyl)-5'-deoxy-5-ethynylcytidine,

N⁴ -[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-ethynylcytidine,

5'-deoxy-5-ethynyl-N⁴ -(neopentyloxycarbonyl)cytidine,

5'-deoxy-N⁴ -[(3,3-dimethylbutoxy)carbonyl]-5-ethynylcytidine,

2',3'-di-O-acetyl-5'-deoxy-5-ethynyl-N⁴ -(n-propoxycarbonyl)cytidine

2',3'-di-O-acetyl-5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxycarbonyl)cytidine

2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine,

2',3'-di-O-acetyl-N⁴ -(ethoxycarbonyl)-5'-deoxy-5-vinylcytidine

2',3'-di-O-acetyl-5'-deoxy-N⁴ -(n-propoxycarbonyl)-5-vinylycytidine,

2',3'-di-O-acetyl-N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-vinylcytidine,

2',3'-di-O-acetyl-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-vinylcytidine,

2',3'-di-O-acetyl-N⁴ -(benzyloxycarbonyl)-5'-deoxy-5-vinylcytidine.

5'-deoxy-5-ethynyl-N⁴ -(n-decyloxycarbonyl)cytidine

5'-deoxy-5-ethynyl-N⁴ -[(2,6-dimethylcyclohexyloxy)-carbonyl]cytidine

5'-deoxy-5-ethynyl-N⁴ -(benzyloxycarbonyl)cytidine

5'-deoxy-5-ethynyl-N⁴ -[(1-isopropyl-2-methyl-propoxy)carbonyl]cytidine

5'-deoxy-5-ethynyl-N⁴ -[(3-methoxybenzyloxy)-carbonyl]cytidine.

The 5'-deoxy-cytidine derivatives of formula (I) can be producedaccording to the following methods. In the following process A-F, P¹represents a hydroxy protecting group such as acetyl, benzoyl,trimethylsilyl, tert-butyldimethylsilyl and the like.

Process A

Compounds represented by the formula (I) wherein R¹, R² and R³ are thesame as defined above can be prepared by reacting a compound representedby the formula (II) ##STR3## [wherein P¹ is a hydroxy-protecting group,and R³ is the same as defined above],

with a compound represented by the formula (III),

    R.sup.4 OCOX                                               (III)

[wherein R⁴ is the same as defined above; X is chloro or bromo], in thepresence of acid acceptor, followed, if necessary, by removal ofprotecting group(s),

Compounds of formula (II) can be prepared by Process D or Process Ebelow. Compounds of formula (III) are known or can be prepared by knownmethods, for example, treatment of the corresponding alcohol withphosgene.

Process B

Compounds represented by the formula (I), wherein R¹ and R² are the sameas defined above and R³ is an ethynyl or vinyl group [which may besubstituted with halogen atom(s), C₁₋₄ alkyl, cycloalkyl, aralkyl, oraromatic ring which may have one or more hetero atom(s)], can also beprepared by reacting a compound represented by the formula (IV) ##STR4##wherein P¹ and R² are the same as defined above], with an acetylene orvinyl derivative in the presence of a palladium catalyst, followed, ifnecessary, by removal of protecting group(s).

Compounds of formula (IV) can be prepared by Process D or Process Ebelow.

Process C

Compounds represented by the formula (I), wherein R¹ and R² are the sameas defined above and R³ is a cyano group, can be prepared by reacting acompound represented by the formula (IV) ##STR5## [wherein P¹ and R² isthe same as defined above], with alkali metal cyanide, followed, ifnecessary, by removal of protecting group(s).

Process D

Compounds represented by the formula (I), wherein R¹ and R³ are the sameas defined above and R² is a hydrogen atom, can also be prepared byreacting a compound represented by the formula (V) ##STR6## [wherein P¹and R³ are the same as defined above], with phosphoryl chloride in thepresence of an acid acceptor, followed by treatment with ammonia,followed, if necessary, by removal of protecting group(s).

Compounds of formula V can be prepared by glycosidation reaction of acorresponding 5-substituted-uracil and protected 5-deoxyribose (VII)according to the procedure described in, for example, J. Kiss et al.,Helvetica Chim. Acta., 65(5) 1522 (1982). 5-substituted-uracils can beprepared as described, for example, in J. Perman et al., TetrahedronLetters, 28, 2427 (1976); V. Farina et al., Synlett., 157 (1991);Biochemical Pharmacology, 38,1471 (1989).

Process E

Compounds represented by the formula (I), wherein R¹, R² and R³ are thesame as defined above, can also be prepared by coupling a compoundrepresented by the formula (VI) ##STR7## [wherein R² and R³ are the sameas defined above], with a compound represented by the formula (VII)##STR8## [wherein p1 is the same as defined above] in the presence ofLewis acid catalyst, followed, if necessary, by removal of protectinggroup(s).

Compounds of formula VI are known [for example, A. S. Jones et al.,Tetrahedron Letters, 28, 2459 (1977] or can be prepared by knownmethods.

Process F

Compounds represented by the formula (I) wherein R³ is a vinyl radical[which may be substituted with halogen atom(s), C₁₋₄ alkyl, cycloalkyl,aralkyl, or aromatic ring which may have one or more hetero atom(s)], R¹and R² are the same as defined above can be prepared by catalytichydrogenation of a compound represented by the formula (VIII) ##STR9##[wherein P¹ is a hydroxy-protecting radical, R³ is an ethynyl radical(which may be substituted with halogen atom(s), C₁₋₄ alkyl, cycloalkyl,aralkyl, or aromatic ring which may have one or more hetero atom(s)),and R² is the same as defined above],

with Lindlar catalyst, followed, if necessary, by removal of protectingradical(s).

Compounds of formula (VIII) can be prepared from the compounds offormula (II) or (IV) by Process B.

In the following, process for producing 5'-deoxy-cytidine derivativesrepresented by the formula (I) according to the present invention willbe explained in more detail.

Process A

Specific examples of the compounds represented by the formula (II)include,

2',3'-di-O-acetyl-5'-deoxy-5-ethynylcytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-ethynylcytidine,

2',3'-di-O-acetyl-5'-deoxy-5-prop-1-ynylcytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-prop-1-ynylcytidine,

2',3'-di-O-acetyl-5-but-1-ynyl-5'-deoxycytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5-but-1-ynyl-5'-deoxycytidine,

2',3'-di-O-acetyl-5'-deoxy-5-pent-1-ynylcytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-pent-1-ynylcytidine,

2',3'-di-O-acetyl-5'-deoxy-5-hex-1-ynylcytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-hex-1-ynylcytidine,

2',3'-di-O-acetyl-5'-deoxy-5-iodocytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodocytidine,

2',3'-di-O-acetyl-5-bromo-5'-deoxycytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5-bromo-5'-deoxycytidine,

2',3'-di-O-acetyl-5-(1-chlorovinyl)-5'-deoxycytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5-(1-chlorovinyl)-5'-deoxycytidine,

2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-vinylcytidine,

2',3'-di-O-acetyl-5'-deoxy-5-trifluoromethylcytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-trifluoromethylcytidine,

2',3'-di-O-acetyl-5-(3-benzyloxybenzyl)-5'-deoxycytidine,

5-(3-benzyloxybenzyl)-2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxycytidine,

2',3'-di-O-acetyl-5-cyano-5'-deoxycytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5-cyano-5'-deoxycytidine and thelike.

The reaction of the compound of the above formula (II) with the compoundof the above formula (III) can be carried out in a solvent such aspyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform,dichloromethane and the like in the presence of an acid acceptor such astriethylamine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine,lutidine and the like. The reaction can be carried out at a temperaturebetween 0 and 30° C.

The protecting group(s) may, if necessary, be removed after the reactionby the procedures known to those skilled in the art, e.g. by basic oracidic hydrolysis, or treatment with fluoride anion.

Process B

Specific examples of the compound represented by the formula (IV)include,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodo-N⁴-(methoxycarbonyl)cytidine,

2',3'-bis-O-(tert-butydimethylsily)-5'-deoxy-N4-(ethoxycarbonyl)-5-iodocytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodo-N⁴-(n-propoxycarbonyl)-cytidine,

N⁴-(n-butoxycarbonyl)-2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodocytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-iodo-N⁴-(n-pentyloxy-carbonyl)-cytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodo-N⁴-(isopentyloxy-carbonyl)-cytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-iodo-N⁴-(n-hexyloxy-carbonyl)-cytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-N⁴-[(2-ethylbutyl)oxycarbonyl]-5-iodocytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodo-N⁴-[(2-phenylethoxy)-carbonyl]cytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-N⁴-[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-iodocytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-iodo-N4-(neopentyloxy-carbonyl)cytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-N4-[(3,3-dimethylbutoxy)-carbonyl]-5-iodocytidine,

2',3'-di-O-acetyl-5'-deoxy-5-iodo-N⁴ -(ethoxycarbonyl)-cytidine,

2',3'-di-O-acetyl-5'-deoxy-5-iodo-N⁴ -(n-propoxycarbonyl)cytidine

2',3'-di-O-acetyl-N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-iodo-cytidine,

2',3'-di-O-acetyl-5'-deoxy-5-iodo-N⁴ -(n-pentyloxycarbonyl)cytidine andthe like.

Specific examples of the acetylene or vinyl derivatives used for thiscoupling reaction are trimethysilyl acetylene, tert-butyidimethysilylacetylene, 1-butyne, 1-pentyne, 1-heptyne, 1-hexyne, 3-methyl-1-butyne,3,3-dimethyl-1-butyne, cyclohexylacetylene, phenylacetylene,3-phenyl-1-propyne, tri-n-butyl(vinyl)stannane and the like.

The coupling reaction of a compound represented by the formula (IV) withan acetylene derivative can be performed in the presence of a palladiumcatalyst such as bis(triphenylphosphine)palladium (II) chloride-copper(I) iodide, bis(triphenylphosphine)palladium(lI) acetate-copper(l)iodide and the like. The coupling reaction of a compound represented bythe formula (IV) with a vinyl derivative can be performed in thepresence of palladium catalyst such astris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium (II)chloride in the presence of tri-2-furylphosphine, triphenylphosphine andthe like.

These reaction can be carried out in a solvent such as chloroform,dichloromethane, tetrahydrofurane, N-methylpyrrolidone,N,N-dimethylformamide and the like. The reaction can be carried out at atemperature between 0 and 80° C., preferably between 10 and 60° C.

Process C

The reaction of the compound of the above general formula (IV) withalkali metal cyanide such as sodium cyanide, potassium cyanide etc. canbe carried out in a solvent such as N,N-dimethylformamide,dimethylsulfoxide, acetonitrile and the like. The reaction can becarried out at a temperature between 0 and 100° C., preferably between10 and 30° C.

Process D

Specific examples of the compounds represented by the formula (V)include,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-ethynyluridine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-prop-1-ynyluridine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5-but-1-ynyl-5'-deoxyuridine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-pent-1-ynyluridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-hex-1-ynyluridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodouridine,

5-bromo-2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxyuridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5-(1-chlorovinyl)-5'-deoxyuridine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-vinyluridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-trifluoromethyluridine,

5-(3-benzyloxybenzyl)-2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxyuridine

2',3'-bis-O-(tert-butyidimethylsilyl)-5-cyano-5'-deoxyuridine and thelike.

The starting materials listed above can be prepared from the known5-substituted uracil derivatives by the method similar to the process Ewherein 5-substituted uracil derivative is used instead of 5-substitutedcytosine derivative.

The reaction of the compound of the above formula (V) with phosphorylchloride can be carried out in a solvent such as pyridine, dioxane,tetrahydrofuran, acetonitrile, chloroform, dichloromethane and the likein the presence of acid acceptor such as triethylamine, pyridine,picoline, 4-(N,N-dimethylamino)pyridine, lutidine, imidazole,N-methylimidazole, triazole and the like at a temparature between 0 and30° C., followed by treatment with aqueous ammonia or ammonia gas in asolvent such as methanol, ethanol, acetonitrile, N,N-dimethylformamideand the like at a temperature between 0 and 30° C.

Process E

Specific examples of the compounds represented by the formula (VI)include 5-ethynylcytosine, 5-prop-1-ynylcytosine, 5-prop-1-ynylcytosine,5-but-1-ynyl-5'-deoxycytosine, 5-pent-1-ynylcytosine,5-hex-1-ynylcytosine, 5-iodocytosine, 5-bromocytosine,5-(1-chlorovinyl)-cytosine, 5-vinylcytosine, 5-trifluoromethylcytosine,5-(3-benzyloxy-benzyl)cytosine, 5-cyanocytosine, 5-ethynyl-N⁴-(n-pentyloxycarbonyl)cytosine and the like.

Specific examples of the compound represented by the formula (VII)include known 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranoside,5-deoxy-1,2,3-tri-O-benzoyl-D-ribofuranoside and the like.

A compound of the formula (VI) may be first converted to thetrimethylsilyl derivative with silylation reagent such ashexamethyldisilazane, followed by the coupling reaction with a compoundrepresented by the formula (VII) in the presence of Lewis acid catalystsuch as tin-(IV)-chloride, titanium-(IV)-chloride and the like. Thiscoupling reaction proceeds in a solvent such as acetonitrile,dichloromethane, chloroform, 1,2-dichloroethane, nitromethane, tolueneand the like, at a temperature between 0 and 30° C., preferably between0 and 10° C.

Process F

Specific examples of the compounds represented by the formula (VIII)include

5'-deoxy-5-ethynylcytidine,

5'-deoxy-N⁴ -(ethoxycarbonyl)-5-ethynylcytidine

5'-deoxy-5-ethynyl-N⁴ -(n-propoxycarbonyl)cytidine,

N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-ethynylcytidine,

5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,

N⁴ -(benzyloxycarbonyl)-5'-deoxy-5-ethynylcytidine,

2',3'-di-O-acetyl-5'-deoxy-5-ethynylcytidine

2',3'-di-O-acetyl-5'-deoxy-5-ethynyl-N⁴ -(ethoxycarbonyl)cytidine,

2',3'-di-O-acetyl-5'-deoxy-5-ethynyl-N⁴ -(n-propoxycarbonyl)cytidine,

2',3'-di-O-acetyl-5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-ethynylcytidine and thelike.

The catalytic hydrogenation of the ethynyl group of the compound offormula (VIII) can be performed using Lindlar catalyst according to themethod known to those skilled in the art [ cf. Synthetic Method, 1952,vol. 7, P38 (Interscience Publishers, Inc., New York)].

The 5'-deoxy-cytidine derivatives of the present invention can be usedas antitumor agent together with known physiologically acceptablepharmaceutical carriers.

The present invention also provides a pharmaceutical compositioncomprising a 5'-deoxy-cytidine derivative represented by the formula (I)and 5-fluorouracil (5-FU) or a derivative thereof. With thiscomposition, the 5'-deoxy-cytidine derivative potentiates the antitumoreffect of 5-fluorouracil or its derivative by delivering a significantlyhigher amount of 5-FU selectively to tumor tissues without significantincrease of 5-FU concentration in plasma.

For the combination of a 5'-deoxy-cytidine derivative represented by theformula (I) with 5-FU or a derivative thereof for the treatment ofcancer with an improved efficacy and safety profile, the 5-FU derivativeis preferably selected from the group consisting of:

5-fluoro-1-(2-tetrahydrofuryl)uracil,

1-(n-hexyloxycarbonyl)-5-fluorouracil,

5'-deoxy-5-fluorouridine,

5'-deoxy-5-fluoro-N⁴ -(n-propoxycarbonyl)cytidine,

N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-fluorocytidine,

5'-deoxy-5-fluoro-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-fluoro-N⁴ -(isopentyloxycarbonyl)cytidine,

5'-deoxy-5-fluoro-N⁴ -(n-hexyloxycarbonyl)cytidine,

5'-deoxy-N⁴ -[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine,

5'-deoxy-5-fluoro-N⁴ -[(2-phenylethoxy)carbonyl]cytidine,

N⁴ -[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-fluorocytidine,

5'-deoxy-5-fluoro-N⁴ -(neopentyloxycarbonyl)-cytidine,

5'-deoxy-N⁴ -[(3,3-dimethylbutoxy)carbonyl]-5-fluorocytidine,

5'-deoxy-5-fluoro-N⁴ -(3,5-dimethylbenzoyl)cytidine,

5'-deoxy-5-fluoro-N⁴ -(3,5-dichlorobenzoyl)cytidine,

2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴ -(n-pentyloxycarbonyl)cytidineand the like.

A compound of the formula (I) can be administered either alone orsimultaneously with 5-FU or a derivative thereof.

Accordingly, the pharmaceutical composition of the present invention canbe obtained by formulating a compound of the formula (I) and 5-FU or aderivative thereof into a single preparation or may be provided in theform of two separate individual preparations.

A pharmaceutical composition of the formula (I) can be administeredbefore or simultaneously with the administration of 5-FU or a derivativethereof; preferably, within 3 hour before or simultaneously with theadministration of 5-FU or a derivative thereof.

In the pharmaceutical composition of the present invention comprising5-FU or a derivative thereof and a 5'-deoxy-cytidine derivativerepresented by the general formula (I), the suitable molar ratio of twocomponents is about 0.001-10 moles, preferably 0.002-0.5 mole of acompound of the formula (I) per mole of 5-FU or its derivative.

The present invention also provides a kit comprising a pharmaceuticalcomposition (component A) containing a compound of the formula (I) and apharmaceutical composition (component B) containing 5-FU or a derivativethereof.

Thus, the present invention is also concerned with pharmaceuticalcompositions of a compound of formula (I) and, pharmaceuticalcompositions with a compound of formula (1) and 5-FU or a derivativethereof, and a kit thereof for the treatment of colorectal cancer,breast cancer, stomach cancer, lung cancer, cervical cancer, bladdercancer and other malignant diseases and the like.

The pharmaceutical compositions and the components A and B of the kit ofthe present invention can be administered in any form, for example,tablets, pills, suppositories, capsules, granules, powders, or emulsionsetc. Pharmaceutically acceptable carriers and excipients useful informulating the pharmaceutical composition of the present invention arethose commonly used. Pharmaceutically acceptable materials can be anorganic or inorganic inert carrier material suitable for enteral,percutaneous or parenteral administration such as water, gelatine, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols and petroleum jelly. The pharmaceutical compositionprovided by the present invention can be administered orally, forexample, in form of tablets, capsules, pills, powders, granules,solutions, syrups, suspensions or elixirs. The administration can alsobe carried out parenterally, for example, in form of sterile solutions,suspensions or emulsions; or locally, for example, in form of solutions,suspensions, salves, powders or aerosols. The pharmaceutical compositioncan be sterilized and/or can contain further adjuvants such aspreserving, stabilizing setting, emulsifying agents, flavor-improvingagents , salts for variation of the osmotic pressure or substancesacting as buffers.

The pharmaceutical composition can be prepared in a conventional manner.

Dosage ranges for the pharmaceutical composition of the presentinvention depend on the route of administration, the age, weight andcondition of the patient and the particular disease to be treated. Inthe case of oral, rectal or parenteral administration for adults, anapproximate daily dosage is in the range of from about 1 mg to about2,000 mg of a compound of formula (I) and from about 10 mg to about4,000 mg of 5-FU or its derivative, depending on the kind of 5-FUderivative used. Oral administration is a preferred route ofadministration of the pharmaceutical composition according to thepresent invention.

The tumor selective delivery of 5-FU through the tumor DPD selectiveinhibition by a compound of formula (I) is evident from the testdescribed hereafter.

1. Tumor DPD Selective Inhibition by Compound A of Example 6

The activity of compound A of Example 6 to inhibit DPD activity wascompared with that of the known DPD inhibitor 5-ethynyluracil (5-EU) inBALB/c nude mice bearing the human prostate cancer xenograft PC-3. Theliver and tumor tissues were resected out from each group of three miceat 2 and 8 hours after the administration of the Compound A (0.5mmol/kg) and 5-EU (0.05 μmol/kg). DPD activity in these tissues was thenmeasured as described elsewhere (Naguib et al., Cancer Research 45,5405-5412, 1985). 5-EU inhibited the DPD activity both in the liver andtumor tissue, whereas compound A strongly inhibited the activity only intumor tissue (Table 1). These results suggest that compound A of Example6 inhibits DPD activity selectively in tumor tissue.

                  TABLE 1                                                         ______________________________________                                        Inhibition of DPD activity by Compound A of Example 6                                 DPD activities (pmol/mg protein/min)                                              Control     5-EU      Compound A                                  Tissues 2 hr   8 hr     2 hr 8 hr   2 hr  8 hr                                ______________________________________                                        Liver   288    162      46   83     177   326                                   Tumor  31  29 17 13  9  9                                                   ______________________________________                                    

2. Selective increase of 5-FU levels in tumors by compound A of Example6 in mice treated with fluoropyrimidines

The experiment shown in Table 2 demonstrates that compound A of Example6 increases 5-FU AUC (Area under curve) selectively in tumors in micetreated with fluoropyrimidines. In this study, fluoropyrimidines, suchas 5-FU, doxifluridine [5'-deoxy-5-fluorouridine] and capecitabine[5'-deoxy-5-fluoro-N⁴ -(n-pentyloxy-carbonyl)cytidine], were given toBALB/c nude mice bearing the human gastric cancer xenograft MKN28 incombination with either compound A or 5-EU. Then, 5-FU levels in theplasma and tumor tissues were measured at 0.25, 0.5, 2, 4 and 7 hoursafter each fluoropyrimidine administration (n=3 mice), and 5-FU AUC wascalculated. The known DPD inhibitor 5-EU greatly increased the 5-FU AUCsboth in the plasma and tumor tissues in mice treated with either 5-FU,capecitabine or doxifluridine. Since the increase of 5-FU levels in theplasma results in the systemic toxicity of 5-FU, 5-EU should enhanceboth the efficacy and toxicity of the fluoropyrimidines.

In contrast, compound A greatly increases the 5-FU AUCs only in tumortissues probably as a result of compound A's tumor selective inhibitionof DPD activity that catabolizes 5-FU. Compound A of Example 6 thereforeenhances the efficacy of fluoropyrimidines with little increasing theirtoxicity.

                  TABLE 2                                                         ______________________________________                                        5-FU AUC in the plasma and tumors                                               in mice treated with fluoropyrimidines                                                                      5-FU AUC                                        Test compounds Fluoropyrimidines (nmolohr/mL)                               (μmol/kg)   (mmol/kg)    Plasma   Tumor                                    ______________________________________                                        Exp. 1                                                                              --           5-FU (0.3)   9.3    1.3                                       Compound A (2) 5-FU (0.3) 9.5 6.0                                             5-EU (1) 5-FU (0.3) 75 48                                                     -- Capecitabine (1.5) 1.3 30                                                  Compound A (2) Capecitabine (1.5) 3.1 67                                      5-EU (1) Capecitabine (1.5) 53 120                                           Exp. 2 -- Doxifluridine (0.75) 2.6 8.0                                         Compound A (2) Doxifluridine (0.75) 11 30                                     5-EU (1) Doxifluridine (0.75) 86 73                                           -- Capecitabine (1.5) 1.5 30                                                  Compound A (2) Capecitabine (1.5) 3.8 76                                      5-EU (1) Capecitabine (1.5) 54 120                                         ______________________________________                                    

3. Enhancement of antitumor activity of Capecitabine by Compound A ofExample 6

Compound A of Example 6 was examined for its activity to enhance theefficacy of capecitabine in BALB/c nude mice bearing the human prostatecancer xenograft PC-3. Compound A and capecitabine were orally givensimultaneously or sequentially 5 successive days per week for 3 weeksstarting on day 53 after the tumor inoculation when the tumor becomespalpable. On day 75, tumor volume gain and the percentage of the tumorgrowth inhibition were calculated. As Table 3 shows, capecitabineinhibited tumor growth to a greater extent when compound A was given incombination either simultaneously or sequentially. Since compound Aitself is not cytotoxic (data not shown), it enhances the efficacy ofcapecitabine by inhibiting DPD activity.

                                      TABLE 3                                     __________________________________________________________________________    Enhancement of Capecitabine Efficacy by compound A of Example 6                             Tumor volume                                                                         Tumor growth                                                                         Body weight                                         Capecitabine Compound A change (mm                                                                             .sup.3) inhibition (%) change (g)                                             Survivors                                    (mmol/kg/d) (μmol/kg/d) Day 53-75 Day 75 Day 75 on Day 75                __________________________________________________________________________    --     --     981    --     -3.6   5/5                                          1.0 -- 757  23 -3.4 5/5                                                       1.0 1.0.sup.  323* 67 -1.8 5/5                                                1.0 1.0.sup.# 201* 80 -0.3 4/5                                              __________________________________________________________________________     *p < 0.05 as compared with the control group                                  .sup.# Compound A was given one hour prior to the capecitabine                administration.                                                          

The following Examples are intended to illustrate the present inventionin more detail, but are not intended to limit its scope in any manner.

Reference example 1:

a) Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-ethynyluridine

5-Ethynyluracil (12 g, 88.2 mmol) was suspended in a solution ofammonium sulfate (570 mg, 4.3 mmol) in hexamethyidisilazane (240 ml).The suspension was refluxed for 6 hr. After concentrating the reactionmixture under reduced pressure, a solution of5-deoxy-1,2,3-tri-O-acetyl-D-ribofranoside (27.5 g, 105.8 mmol) inacetonitrile (300 ml) was added to the residue. Then, a solution ofanhydrous stannic tetrachloride (27.6 g, 105.8 mmol) in nitromethane (60ml) was added dropwise to the mixture with keeping the temperature below0C. After stirring the mixture at 0° C. for additional 4 hr, sodiumbicarbonate was added and followed by dropwise addition of water. Afterthe mixture was stirred for 2 hr, the reaction mixture was filtered toremove insoluble material, which was washed with ethyl acetate. Thefiltrate and washing were combined and dried over MgSO₄ and filtered.The filtrate was evaporated under reduced pressure.

Purification of the residue by silica gel chromatography (usingn-hexane:ethyl acetate=1:2 as an eluent) gave2',3'-di-O-acetyl-5'-deoxy-5-ethynyluridine (13.7 g, 48%yield ).

MALDI-MS: (m/z) 359[M+Na]⁺, 375[M+K]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ 1.47 (3H, d, J=6.6), 2.10 (3H, s), 2.12 (3H,s), 3.23 (1H, s), 4.19-4.28 (1H, m), 5.01-5.05 (1H, m), 5.30-5.34 (1H,m), 5.90 (1H, d, J=4.95), 7.57 (1H, s), 8.34 (1H, br.s)

b) Preparation of2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-ethynyluridine

To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-ethynyluridine (13.7 g,40.7 mmol) was dissolved in methanol (100 ml) was added dropwise asolution of sodium hydroxide (3.3 g, 81.4 mmol) in water (10 ml) withstirring at 0° C. After stirring at 0° C. for additional 30 min, thereaction mixture was adjusted to pH7 with aqueous 1N-hydrochloric acid.Then the mixture was evaporated under reduced pressure.

The residue was dissolved in DMF (250 ml), and imidazole (41.6 g, 610mM) and tert-butyidimethylchlorosilane (30.7 g, 203 mmol) was added tothe solution with stirring. The mixture was continued to stir for 23 hr.The reaction mixture was partitioned between ethyl acetate and water.The aqueous layer was back-extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂ SO₄, filtered andevaporated under reduced pressure. Purification of the residue by silicagel chromatography (using n-hexane:ethyl acetate=3:1 as an eluent) gave2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-ethynyluridine (14.9 g,76% yield).

FAB-MS: (m/z) 481[M+H]⁺,

1H-NMR: (270MHz;CDCl₃): δ 0.10-0.13 (12H, m), 0.91 (18H, m), 1.40 (3H,d, J=6.6), 3.21(1H, s), 3.58 (1H, dd, J=4.29, 6.6), 4.08-4.17 (2H, m),5.62(1H, d, J=2.64), 7.68(1H, s), 8.24(1H, br.s)

The following compounds were prepared in the same manner as describedabove using the corresponding known 5-substituted uracil derivatives:

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodouridine,

FAB-MS: (m/z) 583[M+H]⁺, 605[M+Na]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ -0.09 (3H, s), -0.03 (3H, s), 0.00 (3H, s),0.02 (3H, s), 0.75 (9H,s), 0.81 (9H,s), 1.24 (3H, d, J=6.6), 3.75(1H,dd, J=4.6, 4.0), 3.86 (1H, m), 4.36 (1H, dd, J=5.3, 5.0), 5.59 (I H,d, J=5.6), 7.91 (1H, s), 11.69 (1H, br.s)

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-trifluoromethyluridine,

FAB-MS: (m/z) 525 [M+H]⁺,

¹ H-NMR: (400MHz;CDCl₃): δ 0.00 (6H, s), 0.02 (3H, s), 0.06 (3H, s),0.83 (9H, s), 0.83 (9H, s), 1.32 (3H, d, J=5.9), 3.47 (1H, m), 4.05 (1H,m), 4.16 (1H, m), 5.54 (1H, d, J=2.2), 7.84 (1H, s), 8.43 (1H, br.s)

2',3'-bis-O-(tert-butyidimethylsilyl)-5-(3-benzyloxybenzyl)-5'-deoxy-uridine,

FAB-MS: (m/z) 653 [M+H]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ -0.09-0.01 (12H, m), 0.77-0.82 (18H, m), 0.90(3H, d, J=6.3), 3.27 (1H, m), 3.31 (1H, d, J=16.5), 3.61 (1H, d,J=16.5), 3.86 (1H, m), 3.95 (1H, m), 4.94 (2H, s), 5.50 (1H, d, J=2.0),6.68-6.78 (4H, m), 7.12-7.34 (6H, m), 8.54 (1H, br.s)

The following compounds can be prepared in the same manner as describedabove using the corresponding known 5-substituted uracil derivatives:

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-prop-1-ynyluridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5-but-I -ynyl-5'-deoxyuridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-pent-1-ynyluridine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-hex-1-ynyluridine,

5-bromo-2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxyuridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5-(1-chlorovinyl)-5'-deoxyuridine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-vinyluridine,

EXAMPLE 1

Preparation of2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-ethynylcytidine

To a solution of dimethylaminopyridine (19.0 g, 155.5 mmol) inacetonitrile (120 ml) and pyridine (12.6 ml, 155.5 mmol) phosphorylchloride (14.4 g, 93.8 mM) was added dropwise in an ice bath under Aratmosphere. After stirring the mixture for 1 hour at room temperature, asolution of2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-ethynyluridine (14.9 g,31.1 mmol) in acetonitrile (80 ml) was added at 5° C. with cooling in anice bath. The mixture was stirred at room temperature for 2 hours. Then,25% aq. ammonia solution (10 ml) was added in one portion to thereaction mixture while keeping the temperature below 10° C. A secondportion of 25% aq. ammonia solution (65 ml) was added to the reactionmixture while keeping the temperature below 10° C. The mixture wasstirred at room temperature for 45 minutes. Then the reaction mixturewas diluted with water (200 ml) at room temperature and extracted threetimes with ethyl acetate. The combined organic layers were washedsuccessively with aq. 1N-hydrochloric acid solution, aq. saturatedsodium bicarbonate and brine. The organic layer was dried over MgSO₄,filtered and evaporated under reduced pressure. Purification of theresidue by silica gel chromatography (using n-hexane:ethyl acetate=2:1as an eluent) gave2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-ethynylcytidine (14.8g, 99% yield).

MALDI-MS: (m/z) 502[M+Na]⁺, 518[M+K]⁺,

¹ H-NMR: (400MHz;CDCl₃): δ 0.05 (3H, s), 0.06 (3H, s), 0.12 (3H, s),0.24 (3H, s), 0.89 (9H, s), 0.92 (9H, s), 1.41 (3H, d, J=6.35), 3.36(1H, s), 3.46 (1H, dd, J=3.91,7.81), 4.19-4.26 (2H, m), 5.57 (1H, s),5.79 (1H, br.s), 7.57 (1H, br.s), 7.80(1H, s)

The following compounds were obtained in a manner analogous to that ofExample 1.

EXAMPLE 2

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodocytidine,

FAB-MS: (m/z) 582[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆) δ 0.00 (3H, s), 0.02 (3H, s), 0.06 (3H, s),0.08 (3H, s), 0.82 (9H, s), 0.88 (9H, s), 1.30 (3H, d, J=6.6), 3.78 (1H,dd, J=4.6,4.3), 3.93 (1H, m), 4.33 (1H, dd, J=4.9,4.6), 5.67 (1H, d,J=5.0), 6.67(1H, br.s), 7.87(2H, br.s)

EXAMPLE 3

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-trifluoro-methylcytidine,

FAB-MS: (m/z) 524 [M+H]⁺,

¹ H-NMR: (400MHz;CDCl3): δ 0.00 (6H, s), 0.08 (3H, s), 0.19 (3H, s),0.84 (9H, s), 0.87 (9H, s), 1.35 (3H, d, J=6.6), 3.38 (1H, m), 4.15 (1H,m), 4.21 (1H, m), 5.51 (1H, s), 7.97 (1H, s)

EXAMPLE 4

5-(3-benzyloxybenzyl)-2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxycytidine,

FAB-MS: (m/z) 652 [M+H]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ -0.01 (3H, s), 0.00 (3H, s), 0.09 (3H, s),0.22 (3H, s), 0.86 (9H, s), 0.90 (9H, s), 1.10 (3H, d, J=6.6), 3.37 (1H,m), 3.57 (2H, s), 4.08-4.18 (2H, m), 5.03 (2H, s), 5.59 (1H, s),6.75-6.90 (3H, m), 7.11 (1H, s), 7.26 (1H, m), 7.31-7.44 (5H, m)

EXAMPLE 5

2',3'-bis-O-(tert-butyidimethylsilyl)-5-cyano-5'-deoxycytidine

FAB-MS: (m/z) 481[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ -0.04 (3H, s), 0.00 (3H, s), 0.02 (3H,s),0.76 (9H, s), 0.82 (9H, s), 1.21 (3H, d, J=6.3), 3.81 (1H, m), 4.05 (1H,t, J=5.0), 4.71 (1H, t, J=5.0), 5.65 (1H, d, J=5.3), 6.41 (1H, s), 7.69(1H, br.s), 7.85 (1H, br.s)

The following compounds can be obtained according to a manner analogousto that of Example 5.

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-prop-1-ynylcytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5-but-1-ynyl-5'-deoxycytidine,

2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-pent-1-ynylcytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-hex-1-ynylcytidine,

5-bromo-2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxycytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5-(1-chlorovinyl)-5'-deoxycytidine,

2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-vinylcytidine,

EXAMPLE 6

Preparation of 5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,

a) 2',3'-Bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-ethynylcytidine (45mg, 0.09 mmol) was dissolved in dichloromethane (1 ml) and pyridine (33μl, 0.42 mM). To the mixture, n-pentyl chloroformate (42 mg, 0.28 mmol)was added dropwise in an ice bath under Ar. The reaction mixture wasstirred at room temperature for 2 hours. Water was added and thereaction mixture stirred for 30 minutes. The reaction mixture waspartitioned between dichloromethane and water. The aqueous layer wasextracted with dichloromethane. The combined organic layers were driedover Na₂ SO₄ and filtered. The filtrate was evaporated under reducedpressure.

Purification of the residue by silica gel chromatography (usingn-hexane:ethyl acetate=4: 1 as an eluent) gave2',3'-bis-O-(tert-butyldimethylsilyl)-5'- deoxy-5-ethynyl-N⁴-(n-pentyloxycarbonyl)cytidine (40 mg, 72% yield).

FAB-MS: (m/z) 594[M+H]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ 0.12-0.27 (12H, m), 0.90-0.92 (21H, m),1.26-1.42 (7H, m), 1.64-1.74 (2H, m), 3.25-3.51 (2H, m), 4.15-4.23 (4H,m), 5.55-5.60 (1H, m), 7.62 (0.5H, br.s), 7.73 (0.5H, br.s), 8.00 (0.5H,br.s), 12.3 (0.5H, br.s)

b) To a solution of2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-ethynyl-N⁴-(n-pentyloxycarbonyl)cytidine (19 mg, 0.03 mmol) in tetrahydrofuran(500 μl) was added dropwise tetrabutylammonium fluoride (93 μl, 0.09mmol) [1.0M tetrahydrofuran solution] at room temperature under Aratmosphere. After the mixture was stirred at room temperature for 2hours, the reaction mixture was evaporated under reduced pressure. Theresidue was partitioned between dichloromethane and water. The aqueouslayer was back-extracted with dichloromethane. The combined organiclayers were dried over Na₂ SO₄, filtered and evaporated under reducedpressure. Purification of the residue by silica gel chromatography(using dichloromethane: methanol=20:1 as an eluent) gave5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxy-carbonyl)cytidine (compound A) (9mg, 81% yield).

FAB-MS: (m/z) 366[M+H]⁺,

¹ H-NMR: (400MHz;DMSO-d₆): δ 0.88 (3H, t, J=6.84), 1.30-1.32 (7H, m),1.59-1.63 (2H, m), 3.67-3.71 (1H, m), 3.90-4.46 (5H, m), 5.07 (1H, m),5.42 (1H, m), 5.66 (1H, m), 7.89 (0.5H, br.s), 8.14 (0.5H, br.s), 9.53(0.5H, br.s), 11.7 (0.5H, br.s)

The following compounds (examples 7-41) were obtained in a manneranalogous to that of Example 6.

EXAMPLE 7

5'-deoxy-5-ethyl-N⁴ -(n-pentyloxycarbonyl)cytidine

FAB-MS: (m/z) 370[M+H]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ 0.91(3H, t, J=6.93),1.16 (3H, t, J=7.5), 1.36(4H, m), 1.41 (3H, d, J 6.6), 1.72 (2H, m), 2.47 (2H, q, J=7.5), 3.22(1H, br.s), 3.93 (1H, m), 4.16 (2H, t, J=6.93), 4.28 (2H, m), 4.49 (1H,br.s), 5.66 (1H, d, J=3.63), 7.37 (1H, br.s), 12.46(1H, br.s)

EXAMPLE 8

5'-deoxy-5-iodo-N⁴ -(n-pentyloxycarbonyl)cytidine

FAB-MS: (m/z) 468 [M+H]⁺, 490[M+Na]⁺,

¹ H-NMR: (270 MHz; DMSO-d₆): δ 1.36 (3H, t, J=7.0), 1.76-1.78 (7H, m),2.09 (2H, m), 4.18 (1H, m), 4.36 (1H, m), 4.54 (2H, t, J=5.9), 5.54 (1H,br.d, J=5.0), 5.84 (1H, br.d, J=5.0), 6.09 (1H, d, J=4.3), 8.47 (1H, s),12.24 (1H, br.s)

EXAMPLE 9

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-trifluoromethylcytidine

FAB-MS: (m/z) 410[M+H]⁺,

1H-NMR: (270MHz;CDCl₃): δ 0.88-0.94 (3H, m), 1.32-1.39 (4H, m), 1.42(3H, d, J=6.6), 1.68-1.75 (2H, m), 3.09-3.30 (1H, m), 3.92 (1H, m),4.15-4.27 (5H, m), 5.67 (1H, d, J=3.3), 8.05-8.31 (1H, m), 12.6 (1H,br.s)

EXAMPLE 10

5-(3-benzyloxybenzyl)-5'-deoxy-N⁴ -(n-pentyloxy-carbonyl)cytidine

FAB-MS: (m/z) 538 [M+H]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ 0.90 (3H, t, J=6.9), 1.04 (3H, d, J=6.6),1.26-1.39 (4H, m), 1.72 (2H, m), 3.16 (1H, br.s), 3.67 (1H, d, J=16.5),3.71 (1H, m),3.75 (1H, d, J=16.5), 4.10 (2H, m), 4.16 (2H, t, J=6.9),4.40 (1H, br.s), 5.04 (2H, s), 5.62 (1H, d, J=3.3), 6.79 (1H, d, J=7.6),6.84-6.89 (2H, m), 6.97 (1H, br.s), 7.22-7.43 (6H, m), 12.41 (1H, br.s)

EXAMPLE 11

5-cyano-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine

FAB-MS: (m/z) 367[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆):δ 0.88 (3H, t, J=6.9),1.30 (4H, s), 1.31(3H,d, J 6.3), 1.62 (2H, m), 3.81 (1H, quin., J=6.3), 3.91 (1H, quin.,J=6.3), 4.13 (2H, t, J=6.6),4.39 (1H , m), 5.09 (1H, d, J=6.3), 5.31(1H, d, J=5.3), 5.83(1H, d, J=4.0), 7.57 (1H, s), 11.23 (1H, br.s)

EXAMPLE 12

5'-deoxy-5-ethynyl-N⁴ -(n-propoxycarbonyl)cytidine

FAB-MS: (m/z) 338[M+H]⁺, 360[M+Na]⁺, ¹ H-NMR: (270MHz;DMSO-d₆): δ 0.91(3H, t, J=7.3), 1.31 (3H, d, J=6.3), 1.63 (2H, sextet, J=7.3), 3.69 (1H,dt, J=5.9,5.3), 3.91 (1H, quin., J=5.9), 4.03 (2H, t, J=6.6), 4.13 (1H,dt, J=5.0,4.3), 4.35 (1H, br.s), 5.05 (1H, d, J=5.9), 5.41 (1H, d,J=5.3), 5.66 (1H, d, J=4.0), 8.01 (1H, br.s)

EXAMPLE 13

5'-deoxy-5-ethynyl-N⁴ -(isopropoxycarbonyl)cytidine

FAB-MS: (m/z) 338[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 1.24 (6H, d, J=5.9), 1.31 (3H, d, J=6.6),3.68 (1H, dt, J=5.9,5.6), 3.90 (1H, quin., J=5.9), 4.12 (1H, m), 4.30(1H, s), 4.85 (1H, m), 5.05 (1H, d, J=5.9), 5.40 (1H, d, J=5.3), 5.66(1H, d, J=3.6), 8.02 (1H, br.s)

EXAMPLE 14

N⁴ -(isobutoxycarbonyl)-5'-deoxy-5-ethynylcytidine

FAB-MS: (m/z) 352[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.91 (6H, d, J=6.6), 1.30 (3H, d, J=6.3),1.91 (2H, m), 3.68 (1H, dt, J=5.9,5.3), 3.84 (2H, d, J=6.6), 3.89 (1H,quin., 6.3), 4.11 (1H, m), 4.30 (1H, s), 5.03 (1H, d, J=5.9), 5.38 (1H,d, J=5.3), 5.66 (1H, d, J=4.0), 7.96(1H, s)

EXAMPLE 15

5'-deoxy-5-ethynyl-N⁴ -[(2-methylpentyloxy)carbonyl]-cytidine

FAB-MS: (m/z) 380[M+H]⁺, 402[M+Na]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.85-0.93 (7H, m), 1.31 (3H, d, J 6.3),1.28-1.37 (3H, m), 1.77 (1H, m), 3.69 (1H, dt, J=5.9, 5.6), 3.88(2H, m),3.92(1H, m), 4.13 (1H, dt, J=4.9, 4.6), 4.37(1H, br.s), 5.06 (1H, d,J=5.9), 5.41 (1H, d, J=5.3), 5.66 (1H,d,J=4.0), 8.02 (1H, br.s),

EXAMPLE 16

5'-deoxy-5-ethynyl-N⁴ -[(3-methylpentyloxy)carbonyl]-cytidine

FAB-MS:(m/z) 380[M+H]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ 0.86-0.98 (6H, m), 1.15-1.80 (8H, m),3.25-3.26 (1H, m), 3.53 (1H, brs), 3.90-3.95 (1H, m), 4.25-4.37 (4H, m),5.33 (1H, brs), 5.71 (1H, d, J=4.28), 7.69 (1H, br.s), 8.13 (1H, br.s),

EXAMPLE 17

5'-deoxy-5-ethynyl-N⁴ -[(2-propylpentyloxy)carbonyl]-cytidine

MALDI-MS:(m/z) 408.5[M+H]⁺, 430.5[M+Na]⁺, 446[M+K]⁺

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.87 (6H, br.m), 1.29 (11H, br.m),1.66 (1H,br.m), 3.69 (1H, br.m), 3.94-4.5 (5H, br.m), 5.06 (1H, br.m), 5.42 (1H,br.m), 5.66 (1H, br.m), 7.90 (0.5H, br.s), 8.14 (0.5H, br.s), 9.53(0.5H, br.s)

EXAMPLE 18

5'-deoxy-5-ethynyl-N⁴ -(n-octyloxycarbonyl)cytidine

FAB-MS: (m/z) 408[M+H]⁺, 430[M+Na]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.86 (3H, t, J=5.0), 1.26 (10H, m), 1.31(3H, d, J 6.0), 1.60 (2H, m), 3.69 (1H, dt, J=5.9,5.6), 3.90 (1H, quin.,J=6.3), 4.06 (2H, t, J=6.3), 4.13 (1H, m), 4.35 (1H, br.s), 5.05 (1H, d,J=5.9), 5.41 (1H, d, J=5.3), 5.66 (1H, d, J=4.0), 8.02 (1H, br.s)

EXAMPLE 19

5'-deoxy-N⁴ -[(2-ethylhexyl)oxycarbonyl]-5-ethynyl-cytidine

FAB-MS: (m/z) 408[M+H]⁺,

¹ H-NMR: (270MHz;CDCl₃): δ 0.88-0.94 (6H, m), 1.30-1.41 (12H, m), 3.25(1H, d, J=3.63), 3.53 (1H, m), 3.92-3.94 (1H, m), 4.15-4.37 (4H, m),5.32 (1H, m), 5.70 (1H, dt, J=4.61), 7.86 (1H, br.s), 8.14 (1H, br.s)

EXAMPLE 20

5'-deoxy-5-ethynyl-N⁴ -[(2-phenylethoxy)carbonyl]-cytidine

FAB-MS: (m/z) 400[M+H]⁺,

1H-NMR: (270MHz;DMSO-d₆): δ 1.31 (3H, d, J=6.3), 2.94 (2H, t, J=6.9),3.69 (1H, dt, J=5.9,5.6), 3.90 (1H, quin., J=6.3), 4.14 (1H, m), 4.28(2H, t, J=6.9), 4.31 (1H, br.s), 5.05 (1H, d, J=5.9), 5.41 (1H, d,J=4.9), 5.66 (1H, d, J=4.0), 7.27 (5H, m), 8.01 (1H, br.s),

EXAMPLE 21

N⁴ -(cyclohexyloxycarbonyl)-5'-deoxy-5-ethynylcytidine

FAB-MS: (m/z) 378[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 1.06-1.48 (9H, m), 1.69 (2H, m), 1.86 (2H,m), 3.65-3.72 (1H, m), 3.88-3.93 (1H ,m), 4.13-4.61 (3H, m), 5.06 (1H,d, J=6.27), 5.42 (1H, d, J=4.95), 5.66 (1H, d, J=3.63), 7.9-8.1 (1H, m),9.4 (0.5H, br.s), 11.8(0.5H, br.s)

EXAMPLE 22

N⁴ -[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-ethynylcytidine

FAB-MS: (m/z) 392[M+H]⁺, 414[M+Na]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.86-1.25 (5H, m), 1.31 (3H, d, J=6.3),1.61-1.72 (6H, m), 3.69 (1H, dt, J=5.9,5.6), 3.89 (2H, d, J=6.3), 3.90(1H, m), 4.14 (1H, m), 4.36 (1H, br.s), 5.05 (1H, d, J=5.9), 5.41 (1H,d, J=5.3), 5.66 (1H, d, J=4.0), 8.02 (1H, br.s).

EXAMPLE 23

5'-deoxy-5-ethynyl-N4-(neopentyloxycarbonyl)-cytidine

FAB-MS: (m/z) 366[M+H]⁺, 388[M+Na]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.93 (9H, s), 1.30 (3H, br.d), 3.67-4.27(5.5H, br.m), 4.47 (0.5H, br.s), 5.06 (1H, br.m), 5.39 (1H, br.m), 5.43(1H, br.m), 7.88 (0.5H, br.s), 8.16 (0.5H, br.s), 9.56 (0.5H, br.s),11.69 (0.5H, br.s)

EXAMPLE 24

5'-deoxy-N4-[(3,3-dimethylbutoxy)carbonyl]-5-ethynylcytidine

FAB-MS: (m/z) 380[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 1.01 (9H, s), 1.39 (3H, br.d), 1.63 (2H,br.t), 3.77 (1H, br.m), 3.98-4.32 (4.5H, br.m), 4.56 (0.5H, br.s), 5.13(1H, br.m), 5.45-5.51 (1H, br.m), 5.73-5.75 (1H, br.m), 7.96 (0.5H,br.s), 8.23 (0.5H, br.s), 9.57 (0.5H, br.s), 11.76 (0.5H, br.s)

EXAMPLE 25

5'-deoxy-5-ethynyl-N4-(tridecyloxycarbonyl)cytidine

MALDI-MS: (m/z) 478[M+H]⁺, 516[M+K]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.85(3H, d, J=4.6), 1.24(20H, m), 1.30 (3H,d, J=6.3), 1.60 (2H, m), 3.68 (1H, dt, J=5.9,5.6), 3.90 (1H, quin., J=6.3), 4.05 (2H, t, J=6.6), 4.13 (1H, dt, J=5.0,4.3), 4.34 (1H, br.s),5.05 (1H,d,J=5.9), 5.40(1H,d,J=5.3), 5.65(1H,d,J=3.6), 8.00(1H,br.s)

EXAMPLE 26

N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-ethynylcytidine

FAB-MS: (m/z) 352 [M+H]⁺, 374 [M+Na]⁺,

¹ H-NMR: (270 MHz; DMSO-d₆): δ 0.89 (3H, t, J=7.2), 1.28-1.41 (5H, m),1.53-1.64 (2H, m), 3.64 -3.71 (1H, m), 3.85-3.92 (1H, m), 4.03-4.15 (3H,m), 4.34 (1H, s), 5.04 (1H, d, J=5.9), 5.39 (1H, d, J=5.3), 5.64 (1H, d,J=3.6), 8.06 (1H, br.s)

EXAMPLE 27

5'-deoxy-5-ethynyl-N⁴ -(n-hexyloxycarbonyl)cytidine

FAB-MS: (m/z) 380 [M+H]⁺, 402 [M+Na]⁺,

¹ H-NMR: (270 MHz; DMSO-d₆): δ 0.95 (3H, t, J=6.6), 1.38-1.40 (9H, m),1.63-1.71 (2H, m), 3.74-3.80 (1H, m), 3.94 -4.03 (1H, m), 4.14 (2H, t,J=6.6), 4.19-4.24 (1H, m), 4.43 (1H, s), 5.13 (1H, d, J=5.9), 5.49 (1H,d, J=5.3), 5.74 (1H, d, J=4.0), 8.09 (1H, br.s)

EXAMPLE 28

5'-deoxy-5-ethynyl-N⁴ -(n-decyloxycarbonyl)cytidine

FAB-MS: (m/z) 436 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): d 0.85 (3H, t, J=6.4), 1.15-1.42 (17H, m),1.60 (2H, m), 3.69 (1H, m), 3.90 (1H, m), 4.05 (2H, t, J=6.6), 4.13 (1H,m), 4.34 (1H, br.s), 5.04 (1H, d, J=5.6), 5.40 (1H, d, J=4.9), 5.66 (1H,d, J=3.6), 8.01 (1H, br.s)

EXAMPLE 29

5'-deoxy-5-ethynyl-N⁴ -[(2,6-dimethylcylohexyloxy)-carbonyl]cytidine

FAB-MS: (m/z) 406 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): d 0.83 (36H, d, J=6.3), 1.20-1.50 (9H, m),1.55-1.75 (2H, m), 3.68 (1H, m), 3.93 (1H, m) 4.12-4.20 (2H, m), 4.45(0.7H, s), 4.86 (0.3H, s), 5.04 (1H, d, J=5.6), 5.43 (1H, br.s), 5.67(1H, br.s), 7.96 (0.3H, br.s), 8.14 (0.7H, br.s), 9.50 (0.7H, br.s)12.00 (0.3H, br.s)

EXAMPLE 30

5'-deoxy-5-ethynyl-N⁴ -(benzyloxycarbonyl)cytidine

FAB-MS: (m/z) 386 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): d 1.30 (3H, d, J=6.3), 3.69 (1H, m), 3.89(1H, m), 4.13 (1H, m), 4.35 (1H, br.s), 5.05 (1H, d, J=5.9), 5.14 (2H,s), 5,41 (1H, d, J=5.3), 5.66 (1H, d, J=3.6), 7.31-7.45 (5H, m), 8.01(1H, br.s)

EXAMPLE 31

5'-deoxy-5-ethynyl-N⁴ -[(1-isopropyl-2-methylpropoxy)-carbonyl]cytidine

FAB-MS: (m/z) 394 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): d 0.93 (12H, d, J=6.6), 1.40 (3H, d, J=6.6),1.97 (2H, m), 3.33 (1H, d, J=3.6), 3.55 (1H, s), 3.91 (1H, m), 4.30 (1H,m), 4.36 (1H, m), 4.62 (1H, m), 5.40 (1H, s), 5.72 (1H, d, J=4.3), 7.69(1H, s), 8.11 (1H,s)

EXAMPLE 32

5'-deoxy-5-ethynyl-N⁴ -[(3-methylbenzyloxy)-carbonyl]cytidine

FAB-MS: (m/z) 416 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): d 1.31 (3H, d, J=6.0), 3.70 (1H, m), 3.76(3H, s), 3.90 (1H, m) 4.14 (1H, m), 4.26 (0.5H, br.s), 4.44 (0.5H,br.s), 5.06 (2H, s), 5.16 (1H, br.s), 5.41 (1H, br.s), 5.66 (1H, m),6.91 (1H, d, J=7.9), 7.00 (2H, m), 7.30 (1H, dd, J=7.9, 7.9), 7.89(0.5H, br.s), 8.14 (0.5H, br.s), 9.72 (0.5H, br.s), 11.7 (0.5H, br.s)

EXAMPLE 33

5'-deoxy-5-ethynyl-N⁴ -(methoxycarbonyl)cytidine

FAB-MS: (m/z) 310 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): d 1.30 (3H, d, J=6.3), 3.66 (3H, s), 3.70(1H, m), 3.90 (1H, quin., J=6.3), 4.13 (1H, m), 4.34 (1H, s), 5.05 (1H,d, J=5.9), 5.40 (1H, d, J=5.3) 5.66 (1H, d, J=4.0), 8.00 (1H, br.s)

EXAMPLE 34

5'-deoxy-5-ethynyl-N⁴ -(ethyloxycarbonyl)cytidine

FAB-MS: (m/z) 324 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): d 1.23 (3H, t, J=6.93), 1.31 (3H, d,J=6.27), 3.69 (1H, m), 3.90 (1H, m), 4.08-4.14 (3H, m), 4.35 (1H, br.s),5.05 (1H, d, J=5.94), 5.40 (1H, d, J=5.27), 5.66 (1H, d, J=3.63), 8.02(1H, br.s)

EXAMPLE 35

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine

FAB-MS: (m/z) 342[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ 0.88 (3H, t, J=6.9), 1.31(4H, m), 1.32 (3H,d, J=6.3), 1.55-1.63 (2H, m), 3.63 (1H, dt, J=5.6, 5.6), 3.93 (1H,quin., J=6.3), 3.98 (1H, m), 4.01 (2H, t, J=6.9), 5.04 (1H, d, J=5.9),5.42 (1H, d, J=4.6), 5.73 (1H, d, J=3.0), 7.07 (1H, d, J=7.6), 7.97 (1H,d, J=7.6), 10.66 (1H, br. s)

EXAMPLE 36

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-vinylcytidine

LC-MS: (m/z) 368 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): δ 0.88 (3H, t, J=7.1), 1.31 (7H, m), 1.61(2H, m), 3.74 (1H, m), 3.91 (1H, m), 4.06 (2H, t, J=6.4), 4.22 (1H, m),5.08 (1H, d, J=5.3), 5.20 (1H, d, J=11.3), 5.40 (1H, d, J=4.9), 5.69(1H, d, J=4.0), 5.88 (1H, d, J=17.9), 6.57 (1H, dd, J=11.3, 17.9), 7.78(1H, s), 11.88 (1H, s)

EXAMPLE 37

5'-deoxy-N -(benzyloxycarbonyl)-5-vinylcytidine

FAB-MS: (m/z) 388 [M+H]⁺, 410 [M+Na]⁺,

¹ H-NMR: (270 MHz; DMSO-d₆): δ 1.30 (3H, d, J=6.3), 3.73 (1H, m), 3.92(11H, m), 4.23 (1H, m), 5.13 (2H, s), 5.04-5.22 (2H, m), 5.42 (1H, d,J=5.3), 5.69 (1H, d, J=4.3), 5.69 (1H, dd, J=15.8, 2.0), 6.55 (1H, dd,J=11.2,15.8), 7.36-7.42 (5H, m), 7.78 (1H, s), 11.87 (1H, s).

EXAMPLE 38

N -(ethoxycarbonyl)-5'-deoxy-5-vinylcytidine

FAB-MS: (m/z) 326 [M+H]⁺, 348 [M+Na]⁺,

¹ H-NMR: (270 MHz; DMSO-d₆): δ 1.23 (3H, t, J=7.26), 1.32 (3H, d,J=6.27), 3.70-3.76 (1H, m), 3.89-3.94 (1H, m), 4.11 (2H, q, J=7.26),4.22 (1H, m), 5.09 (1H, d, J=5.61), 5.18-5.22 (1H, m), 5.42 (1H, d,J=5.61), 5.69 (1H, d, J=3.96), 5.85-5.92 (1H, m), 6.57 (1H, dd,J=11.88,17.82), 7.79 (1H, s), 11.88 (1H, br.s)

EXAMPLE 39

5'-deoxy-5-iodo-N⁴ -[(2-phenylethoxy)carbonyl]cytidine

FAB-MS: (m/z) 502 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): δ 1.30 (3H, d, J=6.3), 2.96 (2H, t, J=7.1),3.69 (1H, m), 3.88 (1H, m), 4.17 (1H, m), 4.29 (2H, t, J=7.1), 5.07 (1H,d, J=5.9), 5.38 (1H, d, J=5.3), 5.62 (1H, d, J=4.6), 7.19-7.35 (5H, m),8.01 (1H, s), 11.70 (1H, br.s)

EXAMPLE 40

5'-deoxy-5-iodo-N⁴ -(isopropoxycarbonyl)cytidine

MALDI-MS: (m/z) 462.5 [M+Na]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): δ 1.24 (6H, d, J=6.3), 1.30 (3H, d, J=6.3),3.69 (1H, m), 3.88 (1H, m), 4.17 (1H, m), 4.87 (1H, m), 5.07 (1H, d,J=5.6), 5.38 (1H, d, J=5.3), 5.62 (1H, d, J=4.3), 8.02 (1H, s), 11.77(1H, br.s)

EXAMPLE 41

N⁴ -(cyclohexyloxycarbonyl)-5'-deoxy-5-iodocytidine

LC-MS: (m/z) 479.9 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): δ 1.23-1.42 (6H, m), 1.29 (3H, d, J=6.3),1.70 (2H, m), 1.89 (2H, m), 3.69 (1H, m), 3.88 (1H, m), 4.16 (1H, m),4.60 (1H, m), 5.05 (1H, d, J=5.9), 5.37 (1H, d, J=5.3), 5.62 (1H, d,J=4.3), 8.00 (1H, s)

The following compounds can also be obtained in a manner analogous tothat of Example 6:

5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-prop-1-ynylcytidine,

5-but-1-ynyl-5'-deoxy-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-pent-1-ynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-hex-1-ynyl-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-bromo-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-(1-chlorovinyl)-N⁴ -(n-pentyloxycarbonyl)cytidine,

5'-deoxy-5-ethynyl-N⁴ -(isopentyloxycarbonyl)cytidine, and

5'-deoxy-N⁴ -[(2-ethylbutyl)oxycarbonyl]-5-ethynylcytidine.

EXAMPLE 42

Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-iodocytidine

5-Iodocytosine (1.0 g; 4.22 mmol) and a catalytic amount of (NH₄)₂ SO₄were suspended in a solution of toluene (10 ml) and hexamethyidisilazane(20 ml). The suspension was heated at 110° C. for 18 hours to become aclear solution. After concentrating the reaction solution under reducedpressure, acetonitrile (25 ml) and5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranoside (1.32 g; 5.06 mmol) wereadded to residue. Then, anhydrous stannic chloride(0.58 ml; 5.06 mmol)in nitromethane (5 ml) was added dropwise to the mixture over 5 minutes.During the addition, the mixture was kept below 0° C. by ice cooling.After stirring the mixture at 0˜5° C. for 2 hours, 2 g of sodiumbicarbonate was added, followed by dropwise addition of water (0.7 ml).After the addition, the mixture was stirred vigorously at roomtemperature for 30 minutes. The reaction mixture was filtered to removeinsoluble material, which was washed with CH₂ Cl₂. The filtrate andwashing were combined, and washed with water and sat.aq. sodiumbicarbonate, and then dried over Na₂ SO₄ and filtered. The filtrate wasevaporated under reduced pressure. The crude product was purified byflash chromatography on SiO₂ (eluent: 5% MeOH / CH₂ Cl₂) to give5'-deoxy-2',3'-di-O-acetyl-5-iodocytidine as a colorless solid. (1.22 g,66% yield)

FAB-MS:(m/z) 438[M+H]⁺, 460[M+Na]⁺,

1H-NMR: (270MHz;DMSO-d₆): δ 1.32(3H, d, J=6.3), 2.04(3H, s), 2.06(3H,s), 4.02(1H, quin., J=6.3), 5.14(1H, t, J=6.6), 5.48(1H, dd, J=6.6,4.3), 5.69(1H, d, J=4.0), 6.78(1H, br.s), 8.01(1H, br.s), 8.11(1H, s)

EXAMPLE 43

Preparation of 2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodo-N⁴-(n-pentyloxycarbonyl)cytidine

a) 5'-deoxy-2',3'-di-O-acetyl-5-iodocytidine (200 mg; 0.46mmol) wasdissolved in methanol (5 ml). To this solution 1 mol/l sodium hydoxidesolution was added dropwise at 0° C. After stirring for 10 minutes, thereaction mixture was adjusted to pH 7 with 1N-hydrochloric acidsolution. The reaction mixture was evaporated under reduced pressure.

A mixture of imidazole(467 mg; 6.9 mmol) in DMF(5 ml) was added to theresidue. Then tert-butyidimethylchlorosilane(345 mg; 2.29 mmol) wasadded to the mixture. The reaction mixture was stirred at 50° C. for 1hour. The mixture was extracted with dichloromethane, washed with waterand then dried over Na₂ SO₄ and filtered. The filtrate was evaporatedunder reduced pressure. The crude product was purified by flashchromatography on SiO₂ (eluent :70% EtOAc/n-hexane to 100% EtOAc) togive 5'-deoxy-2',3'-di-O-tert-butyldimethysilyl-5-iodocytidine as acolorless solid. (176.5 mg, 66 % yield)

FAB-MS: (m/z) 582[M+H]⁺,

¹ H-NMR: (270MHz;DMSO-d₆) δ 0.00 (3H, s), 0.02 (3H, s), 0.06 (3H, s),0.08 (3H, s), 0.82 (9H, s), 0.88 (9H, s), 1.30 (3H, d, J=6.6), 3.78 (1H,dd, J=4.6, 4.3), 3.93 (1H, m), 4.33 (1H, dd, J=4.9, 4.6), 5.67 (1H, d,J=5.0), 6.67(1H, br.s), 7.87(2H, br.s)

b) To a stirred solution of5'-deoxy-2',3'-bis-O-(tert-butyidimethylsilyl)-5-iodocytidine (116 mg,0.200 mmol) in CH₂ Cl₂ (2 ml) pyridine (84 μl, 1.00 mmol),N,N-dimethylamino-pyridine (6 mg, 0.05 mmol), and n-pentyl chloroformate(95 μl, 0.600 mmol) was added at room temperature under Ar. Afterstirring for 30 minutes, the reaction mixture was partitioned withdichloromethane and water and the organic phase was separated and thewater phase was extracted with CH₂ Cl₂ (15 ml×4). The combined organicphase was washed with water and brine, dried over Na₂ SO₄ and filtered.The filtrate was evaporated under reduced pressure. The crude productwas purified by flash chromatography on SiO₂ (eluent: 20%EtOAc/n-hexane) to give2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-iodo-N⁴-(n-pentyloxycarbonyl)cytidine as a colorless amorphous solid. (132.4mg, 91 % yield)

FAB-MS: (m/z) 696 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆): δ 0.00 (3H, s), 0.03 (3H, s), 0.05 (3H, s),0.07 (3H, s), 0.77 (9H, s), 0.81 (9H, s), 1.20-1.27 (10H, m), 1.46-1.55(2H, m), 3.74 (1H, dd, J=4.6, 4.6), 3.89-4.01 (3H, m), 4.37 (1H, dd,J=4.5, 4.6), 5.55 (1H, d, J=4.6), 7.92 (1H, s), 11.70 (1H, br.s)

EXAMPLE 44

Preparation of2',3'-bis-O-(tert-butylidimethylsilyl)-5'-deoxy-5-[(trimethylsilyl)-ethynyl]-N⁴-(n-pentyloxycarbonyl)cytidine

To a solution of2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-iodo-N⁴-(n-pentyloxycarbonyl)cytidine (130 mg, 0.18 mmol) in CH₂ Cl₂ (2 ml) andEt₃ N(2 ml) Cul (10.7 mg, 0.1056 mmol), Pd(PPh₃)₂ Cl₂ (2.6 mg, 0.0036mmol), and trimethylsilyl-acetylene (58.6 μl, 0.40 mmol) were added andstirred for 2 hours at room temperature under Ar in the dark. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in EtOAc(25 ml×3), washed with 2% aq. EDTA.2Na(10 ml×2),water and brine, dried over Na₂ SO₄ and filtered. The filtrate wasevaporated under reduced pressure. The crude product was purified byflash chromatography on SiO₂ (eluent: 10% EtOAc/n-hexane) to give2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-[(trimethylsilyl)ethynyl]-N⁴-(n-pentyloxycarbonyl)-cytidine as a colorless amorphous solid. (30.2mg, 26% yield)

FAB-MS: (m/z) 666[M+H]⁺, 688[M+Na]⁺,

¹ H-NMR: (270MHz;DMSO-d₆): δ -0.18 (3H, s), -0.16 (3H, s), -0.14 (3H,s),-0.12 (3H,s), 0.00 (9H,s), 0.64 (9H, s), 0.65 (3H, s), 0.67 (9H, s),1.01(4H, m), 1.14 (3H, d, J=6.6), 1.40 (2H, m), 3.58 (1H, t, J=4.9),3.79 (1H, m), 3.87 (2H, m), 4.20 (1H, m), 5.43 (1H, d, J=3.6), 7.88 (1H,br.s)

EXAMPLE 45

5'-deoxy-2',3'-bis-O-(tert-butyidimethylsilyl)-5-cyanocytidine

To a stirred solution of 5'- deoxy-2',3'-bis-(O-tert-butyidimethylsilyloxy)-5-iodocytidine (153 mg, 0.263mmol) in DMF (5 ml) NaCN (34.3 mg, 0.70 mmol) was added at roomtemperature. After stirring for 1 day, the reaction mixture wasconcentrated under reduced pressure. The crude product was dissolved inEtOAc, and then washed with water and brine. The extract was dried overNa₂ SO₄ and filtered. The filtrate was concentrated under reducedpressure. The crude product was purified by flash chromatography on SiO₂(eluent: EtOAc) to give5'-deoxy-2',3'-bis-O-(tert-butyldimethylsilyl)-5-cyanocytidine as a paleyellow solid. (71.1 mg, 56 % yield)

FAB-MS: (m/z) 481[M+H]⁺,

1H-NMR: (270MHz; DMSO-d₆): δ -0.04 (3H, s), 0.00 (3H, s), 0.02 (3H,s),0.76 (9H, s), 0.82 (9H, s), 1.21 (3H, d, J=6.3), 3.81 (1H, m), 4.05 (1H,t, J=5.0), 4.71 (1H, t, J=5.0), 5.65 (1H, d, J=5.3), 6.41 (1H, s), 7.69(1H, br.s), 7.85 (1H, br.s)

EXAMPLE 46

Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine

To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-iodocytidine (1.6 g, 3.66mmol) in 10 ml DMF were added Pd₂ (dba)₃ (67 mg, 0.073 mmol) andtri-2-furylphosphine (85 mg, 0.366 mmol) and tri-n-butyl(vinyl)stannane(2.1 ml, 7.318 mmol ) under Ar atmosphere at room temperature. Afterstirring for 19 hours, tri-n-butyl(vinyl)stannane (2.1 ml, 7.318 mmol )was added to the reaction mixture, and then the reaction mixture waswarmed up to 40° C. with stirring for 24 hours. The solvent was removedin vacuo, and the residue was purified on a column of silica gel(eluent: ethyl acetate ˜CH₂ Cl_(2:) MeOH=95: 5) to give2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine (1.13 g, 92 %) as colorlesssolid:

FAB-MS: (m/z) 338 [M+H]⁺,

1H-NMR: (270MHz; DMSO-d₆): d 1.33 (3H, d, J=6.3), 2.05 (3H, s ), 2.06(3H, s), 4.05 (1H, quin., J=6.3), 5.14 (1H, d, J=10.8), 5.16 (1H, t,J=6.6), 5.54 (1H, d, J=17.2 ), 5.53 (1H, dd, J=6.9, 5.9 ), 5.73 (1H, d,J=4.3 ), 6.55 (1H, dd, J=17.2, 10.8 ),7.20 (1H, br. s ),7.57 (1H, br. s),7.88 (1H, s)

EXAMPLE 47

Preparation of 5'-deoxy-5-vinylcytidine

To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine (111 mg,3.29 mmol) in 5 ml of methanol was added 1N NaOH (0.32 ml, 0.32 mmol) atroom temperature. After stirring for 1 hour, 1N HCl (ca.0.3 ml) wasadded to the reaction mixture, and then the reaction mixture wasconcentrated under reduced pressure. The residue was purified by solidphase extraction (MEGA Bond Elute LRC, eluent: H₂ O˜H₂ O: MeOH=1: 1,step gradient) to give 5'-deoxy-5-vinylcytidine (82 mg, 98%) ascolorless solid:

LC-MS:(m/z) 253.9 [M+H]⁺,

¹ H-NMR: (270MHz; DMSO-d₆ ): d 1.29 (3H, d, J=6.3 ), 3.68 (1H, m ), 3.86(1H, m), 4.08 (1H, m), 4.97 (1H, d, J=5.9), 5.12 (1H, d, J=11.1 ), 5.28(1H, d, J=5.3), 5.50 (1H, d, J=17.2 ), 5.70 (1H, d, J=3.6), 6.58 (1H,dd, J=11.1,17.2), 7.10 (1H, br.s), 7.42 (1H, br.s), 7.64 (1H, s)

The following examples illustrate pharmaceutical preparations containinga compound provided by the present invention.

EXAMPLE A

Interlocking gelatin capsules each containing the following ingredientswere manufactured in a known manner:

    ______________________________________                                        5'-Deoxy-5-ethynyl-N.sup.4 -(n-pentyloxycarbonyl)-                                                    40 mg                                                   cytidine                                                                      Lactose 70 mg                                                                 Corn starch 25 mg                                                             Magnesium stearate  1 mg                                                      Crospovidone  4 mg                                                             140 mg                                                                     ______________________________________                                    

EXAMPLE B

Interlocking gelatin capsules each containing the following ingredientswere manufactured in a known manner:

    ______________________________________                                        5'-Deoxy-5-fluoro-N.sup.4 -(n-pentyloxycarbonyl)-                                                     100 mg                                                  cytidine                                                                      5'-Deoxy-5-ethynyl-N.sup.4 -(n-pentyloxycarbonyl)- 10 mg                      cytidine                                                                      Lactose 70 mg                                                                 Corn starch 25 mg                                                             Magnesium stearate  1 mg                                                      Crospovidone  4 mg                                                             210 mg                                                                     ______________________________________                                    

EXAMPLE C

Tablets each containing the following ingredients were manufactured in aknown manner:

    ______________________________________                                        5'-Deoxy-5-ethynyl-N.sup.4 -(n-pentyloxycarbonyl)-                                                    40 mg                                                   cytidine                                                                      Lactose 70 mg                                                                 Magnesium stearate  3 mg                                                      Crospovidone  7 mg                                                            Povidone 10 mg                                                                 130 mg                                                                     ______________________________________                                    

If necessary, the tablet is film-coated with hydroxypropylmethylcellulose, talc and colorant.

EXAMPLE D

Tablets each containing the following ingredients were manufactured in aknown manner:

    ______________________________________                                        5'-Deoxy-5-fluoro-N.sup.4 -(n-pentyloxycarbonyl)-                                                     300 mg                                                  cytidine                                                                      5'-Deoxy-5-ethynyl-N.sup.4 -(n-pentyloxycarbonyl)- 20 mg                      cytidine                                                                      Lactose 70 mg                                                                 Magnesium stearate  3 mg                                                      Crospovidone  7 mg                                                            Povidone 10 mg                                                                 186 mg                                                                     ______________________________________                                    

If necessary, the tablet is film-coated with hydroxypropylmethylcellulose, talc and colorant.

What is claimed is:
 1. A compound of the formula (I) ##STR10## whereinR¹ is a hydrogen atom or a group easily hydrolyzable under physiologicalconditions; R² is a hydrogen atom, or --CO--OR⁴ group wherein R⁴ is asaturated or an unsaturated, a straight or a branched hydrocarbon groupconsisting of one to fifteen carbon atoms, or a group of theformula--(CH₂)_(n) --Y (in which Y is cyclohexyl or phenyl; n is aninteger from 0 to 4); R³ is selected from the group consisting of ahydrogen atom, bromo, iodo, cyano, an unsubstituted C₁₋₄ alkyl group, asubstituted C₁₋₄ alkyl group, an unsubstituted vinyl group,monosubstituted vinyl group, disubstituted vinyl group, trisubstitutedvinyl group, unsubstituted ethynyl group, and a monosubstituted ethynylgroup; wherein the C₁₋ 4 alkyl substituents are one or more halogroup(s); and wherein the vinyl and ethynyl substitutents areindependently selected from the group consisting of a halo group, a C₁₋₄alkyl, a cycloalkyl, an aralkyl, an aromatic ring, and a heteroaromaticring with one or more heteroatoms; with the proviso that R² and R³ donot simultaneously mean a hydrogen atom.
 2. A compound of claim 1,wherein R¹ is selected from the group consisting of hydrogen, acetyl,propionyl, benzoyl, toluoyl, glycyl, alanyl, p-alanyl, valyl, and lysyl.3. A compound of claim 2, wherein R¹ is hydrogen or acetyl.
 4. Acompound of claim 1, wherein R² is a hydrogen atom.
 5. A compound ofclaim 1, wherein R² is a --CO--OR⁴ group wherein R⁴ is a saturated or anunsaturated, a straight or branched hydrocarbon group consisting of oneto fifteen carbon atoms, or R⁴ is a group of the formula --(CH₂)_(n) --Yin which Y is cyclohexyl or phenyl, and n is an integer from 0 to
 4. 6.A compound of claim 5, wherein R² is a --CO--OR⁴ group wherein R⁴ isselected from the group consisting of methyl, ethyl, n-propyl,1-isopropyl-2-methylpropyl, 1,1,2-trimethylpropyl, n-butyl, isobutyl,2-ethylbutyl, 3,3-dimethyl-butyl, n-pentyl, isopentyl, neopentyl,2-propylpentyl, n-hexyl, 2-ethylhexyl, n-heptyl, n-octyl, allyl,2-buten-1-yl, 3-buten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 3-hexen-1-yl,4-hexen-1-yl, 5-hexen-1-yl, and n-tridecyl.
 7. A compound of claim 1,wherein R² is a --CO--OR⁴ group wherein R⁴ is selected from the groupconsisting of cyclohexyl, cyclohexylmethyl, 2-cyclohexyl,3-cyclohexylpropyl, 4-cyclohexylbutyl, phenyl, benzyl, phenethyl,3-phenylpropyl, and 4-phenylbutyl.
 8. A compound of claim 1, wherein R²is a --CO--OR⁴ group wherein R⁴ is selected from the group consisting ofn-propyl, n-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3,3-dimethylbutyl, 2-ethylbutyl, phenylethyl and cyclohexylmethyl.
 9. Acompound of claim 1, wherein R³ is selected from the group consisting ofthe hydrogen atom, bromo, iodo, and cyano.
 10. A compound of claim 1,wherein R³ is a C₁ -C₄ alkyl group which is unsubstituted or substitutedwith one or more halogen atom(s).
 11. A compound of claim 10, wherein R³is selected from the group consisting of methyl, trifluoromethyl, ethyl,and propyl.
 12. A compound of claim 1, wherein R³ is selected from thegroup consisting of an unsaturated vinyl group, a monosubstituted vinylgroup, a disubstituted vinyl group, a trisubstituted vinyl group, anunsubstituted ethynyl group, and a mono-substituted ethynyl group,wherein the vinyl and ethynyl substitutents are independently selectedfrom the group consisting of a halo group, a C₁₋₄ alkyl, a cycloalkyl,an aralkyl, an aromatic ring, and a heteroaromatic ring with one or moreheteroatoms.
 13. A compound of claim 12, wherein R³ is selected from thegroup consisting of vinyl, 1-chlorovinyl, 2-bromovinyl,2-bromo-1-chlorovinyl, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl,hex-1-ynyl, 3,3-dimethyl-but-1-ynyl, cyclo-pentylethynyl, phenylethynyl,3-phenylprop-1-ynyl, pyrid-2-ylethynyl and imidazol-2-ylethynyl.
 14. Acompound of claim 1, wherein R³ is selected from the group consisting ofethynyl, vinyl and iodo.
 15. A compound of claim 1,5'-deoxy-5-ethynyl-N⁴ -{(3-methoxy-benzyloxy)-carbonyl}cytidine.
 16. Acompound of claim 1, wherein R³ is selected from the group consisting ofa hydrogen atom, bromo, iodo, trifluoromethyl, ethyl, propyl, cyano,vinyl, 1-chlorovinyl, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl,hex-1-ynyl and, bromoethynyl.
 17. A compound of claim 1,5'-deoxy-5-ethynylcytidine.
 18. A compound of claim 1,5'-deoxy-5-prop-1-ynylcytidine.
 19. A compound of claim 1,5-but-1-ynyl-5'-deoxycytidine.
 20. A compound of claim 1,5'-deoxy-5-pent-1-ynylcytidine.
 21. A compound of claim 1,5'-deoxy-5-hex-1-ynylcytidine.
 22. A compound of claim 1,5'-deoxy-5-iodocytidine.
 23. A compound of claim 1,5-bromo-5'-deoxycytidine.
 24. A compound of claim 1,5-(1-chlorovinyl)-5'-deoxycytidine.
 25. A compound of claim 1,5'-deoxy-5-vinylcytidine.
 26. A compound of claim 1,5'-deoxy-5-trifluoromethylcytidine.
 27. A compound of claim 1,5-cyano-5'-deoxycytidine.
 28. A compound of claim 1, 5'-deoxy-N⁴-(n-pentyloxycarbonyl)cytidine.
 29. A compound of claim 1, 5'-deoxy-N⁴-(n-pentyloxycarbonyl)-5-prop-1-ynylcytidine.
 30. A compound of claim 1,5-but-1-ynyl-5'-deoxy-N⁴ -(n-pentyloxy-carbonyl)cytidine.
 31. A compoundof claim 1, 5'-deoxy-5-pent-1-ynyl-N⁴ -(n-pentyloxy-carbonyl)cytidine.32. A compound of claim 1, 5'-deoxy-5-hex-1-ynyl-N⁴-(n-pentyloxy-carbonyl)cytidine.
 33. A compound of claim 1,5'-deoxy-5-iodo-N4-(n-pentyloxycarbonyl)-cytidine.
 34. A compound ofclaim 1, 5-bromo-5'-deoxy-N⁴ -(n-pentyloxy-carbonyl)cytidine.
 35. Acompound of claim 1, 5-(1-chlorovinyl)-5'-deoxy-N⁴-(n-pentyloxy-carbonyl)cytidine.
 36. A compound of claim 1, N⁴-(ethoxycarbonyl)-5'-deoxy-5-vinylcytidine.
 37. A compound of claim 1,5'-deoxy-N⁴ -(n-propoxycarbonyl)-5-vinyl-cytidine.
 38. A compound ofclaim 1, N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-vinyl-cytidine.
 39. Acompound of claim 1, 5'-deoxy-N⁴-(n-pentyloxycarbonyl)-5-vinyl-cytidine.
 40. A compound of claim 1, N⁴-(benzyloxycarbonyl)-5'-deoxy-5-vinyl-cytidine.
 41. A compound of claim1, 5'-deoxy-N⁴ -(n-pentyloxycarbonyl)-5-trifluoromethylcytidine.
 42. Acompound of claim 1, 5-cyano-5'-deoxy-N⁴-(n-pentyloxy-carbonyl)cytidine.
 43. A compound of claim 1,5'-deoxy-5-ethynyl-N⁴ -(methoxycarbonyl)-cytidine.
 44. A compound ofclaim 1, 5'-deoxy-N⁴ -(ethoxycarbonyl)-5-ethynyl-cytidine.
 45. Acompound of claim 1, 5'-deoxy-5-ethynyl-N⁴-(n-propoxy-carbonyl)cytidine.
 46. A compound of claim 1,5'-deoxy-5-ethynyl-N⁴ -(isopropoxy-carbonyl)cytidine.
 47. A compound ofclaim 1, N⁴ -(n-butoxycarbonyl)-5'-deoxy-5-ethynyl-cytidine.
 48. Acompound of claim 1, 5'-deoxy-5-ethynyl-N⁴-(isobutoxycarbonyl)-cytidine.
 49. A compound of claim 1,5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxy-carbonyl)cytidine.
 50. A compound ofclaim 1, 5'-deoxy-5-ethynyl-N⁴ -[(2-propyl-pentyloxy)carbonyl]cytidine.51. A compound of claim 1, 5'-deoxy-5-ethynyl-N⁴-(isopentyloxy-carbonyl)cytidine.
 52. A compound of claim 1,5'-deoxy-5-ethynyl-N⁴ -{(2-methyl-pentyloxy)carbonyl}cytidine.
 53. Acompound of claim 1, 5'-deoxy-5-ethynyl-N⁴-{(3-methyl-pentyloxy)carbonyl}cytidine.
 54. A compound of claim 1,5'-deoxy-5-ethynyl-N⁴ -(n-hexyloxy-carbonyl)cytidine.
 55. A compound ofclaim 1, 5'-deoxy-N4-{(2-ethylbutyl)oxycarbonyl}-5-ethynylcytidine. 56.A compound of claim 1, 5'-deoxy-N⁴-{(2-ethylhexyl)oxycarbonyl}-5-ethynylcytidine.
 57. A compound of claim1, 5'-deoxy-5-ethynyl-N⁴ -{(2-phenylethoxy)-carbonyl}cytidine.
 58. Acompound of claim 1, N⁴-(cyclohexyloxycarbonyl)-5'-deoxy-5-ethynylcytidine.
 59. A compound ofclaim 1, N⁴ -{(cyclohexylmethoxy)carbonyl}-5'-deoxy-5-ethynylcytidine.60. A compound of claim 1, 5'-deoxy-5-ethynyl-N⁴-(neopentyloxy-carbonyl)cytidine.
 61. A compound of claim 1, 5'-deoxy-N⁴-{(3,3-dimethylbutoxy)carbonyl}-5-ethynylcytidine.
 62. A compound ofclaim 1, 2',3'-di-O-acetyl-5'-deoxy-5-ethynyl-N⁴-(n-propoxycarbonyl)cytidine.
 63. A compound of claim 1,2',3'-di-O-acetyl-5'-deoxy-5-ethynyl-N⁴ -(n-pentyloxycarbonyl)-cytidine.64. A compound of claim 1, 2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine.65. A compound of claim 1, 2',3'-di-O-acetyl-N⁴-(ethoxycarbonyl)-5'-deoxy-5-vinylcytidine.
 66. A compound of claim 1,2',3'-di-O-acetyl-5'-deoxy-N⁴ -(n-propoxy-carbonyl)-5-vinylcytidine. 67.A compound of claim 1, 2',3'-di-O-acetyl-N⁴-(n-butoxycarbonyl)-5'-deoxy-5-vinylcytidine.
 68. A compound of claim 1,2',3'-di-O-acetyl-5'-deoxy-N⁴ -(n-pentyloxy-carbonyl)-5-vinylcytidine.69. A compound of claim 1, 2',3'-di-O-acetyl-N⁴-(benzyloxycarbonyl)-5'-deoxy-5-vinylcytidine.
 70. A compound of claim1, 5'-deoxy-5-ethynyl-N⁴ -(n-decyloxy-carbonyl)cytidine.
 71. A compoundof claim 1, 5'-deoxy-5-ethynyl-N⁴-{(2,6-dimethylcyclo-hexyloxy)-carbonyl}cytidine.
 72. A compound ofclaim 1, 5'-deoxy-5-ethynyl-N⁴ -(benzyloxy-carbonyl)cytidine.
 73. Acompound of claim 1, 5'-deoxy-5-ethynyl-N⁴-{(1-isopropyl-2-methyl-propoxy)carbonyl}cytidine.